We are conducting a case-control study of PD nested in the Agricultural Health Study (AHS). The parent AHS is a cohort study of 89,000 licensed pesticide applicators and their spouses, recruited in 1993-97, which was designed to evaluate the importance of farming-related exposures to cancer and other chronic diseases. The specific aims of the nested case-control study are to examine the relationship of PD (i) to pesticide exposure; (ii) to other neurotoxicants, particularly metals; (iii) to lifestyle factors including diet, smoking, and caffeine; (iv) to skin melanin, to examine racial/ethnic differences; and (v) to polymorphisms in genes involved in xenobiotic metabolism, dopaminergic neurotransmission, or xenobiotic-specific membrane transport. [unreadable] [unreadable] Field work for the case-control study is complete; we have enrolled 115 cases and 384 controls. Suspect cases were identified using information from the AHS, and the diagnosis of PD was verified using an in-home neurologic exam and medical records. Controls were a random sample from the remaining cohort, matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources. We used interview information on pesticide use, other exposures, and lifestyle already collected in the AHS. In addition, we collected blood samples to measure organochlorines and metals and for DNA banking, and samples of house and farm equipment dust to measure certain pesticides and metals. We also conducted telephone interviews to obtain information on lifetime use of specific pesticides implicated in PD by case reports or animal research as well as exposure to other neurotoxicants. FAME is the first study to use prospectively collected exposure information to evaluate the hypothesis that pesticide exposure is related to PD risk. It exploits the unique opportunity provided by the AHS to address this issue in an occupational group defined by pesticide use, combining rigorous methods of case-finding with several complementary methods of exposure assessment. [unreadable] [unreadable] In an initial analysis, we evaluated cross-sectional and prospective data collected in the AHS, using self-reported PD as an outcome. We used data from 84,000 licensed private pesticide applicators and their spouses enrolled in the Agricultural Health Study (AHS) to evaluate the relationship of self-reported PD to pesticide exposure. Cohort members provided detailed information on lifetime pesticide use at enrollment and reported physician-diagnosed PD both at enrollment (prevalent cases, n=83) and five years later (incident cases, n=78); self-reported PD cases were compared to the remaining cohort. Prevalent cases were more likely to report parkinsonian symptoms including hand tremor. Incident cases also reported increased hand tremor at enrollment, five years before reporting PD. Incident PD was associated with cumulative days of pesticide use at enrollment (OR: 2.3; 95%CI: 1.2,4.5 for highest vs lowest quartile; p for trend 0.009), with personally applying pesticides more than half the time (OR: 1.9; 95%CI: 0.7,4.7), and with some specific pesticides (ORs > 1.4). Receiving pesticide-related medical care was associated with increased risk, and using personal protective equipment to reduce potential exposure was associated with decreased risk. This study provides further support for the hypothesis that exposure to certain pesticides increases PD risk. Findings for specific chemicals must be interpreted cautiously but may provide fruitful leads for further investigation. This analysis is limited by its use of self-reported diagnoses of PD, a problem that will be addressed in our case-control study, which has neurologist-confirmed cases. [unreadable] [unreadable] We investigated the relationship of blood metal levels to PD. An earlier study reported higher whole blood levels of copper, iron, magnesium, and zinc in PD cases compared to controls. We measured whole blood metal levels using inductively coupled plasma-mass spectrometry in 99 confirmed PD cases and 116 matched controls. The mean time between diagnosis and blood collection was 7.4 years. Seven of ten elements analyzed were detected in almost all subjects (copper, iron, lead, magnesium, manganese, selenium, and zinc). While we saw expected associations of metals with known predictors (eg, lead and smoking, lead and age), we observed no differences in blood metal levels between cases and controls. Further, the values that we found for both cases and controls are similar to those reported for cases in the earlier study. Among cases, we saw no differences related to time since diagnosis. The half-life of metals in blood is relatively short, and the latency between metal exposure and disease may be long. Thus measuring current blood levels may not reflect the etiologically relevant time-window. In conclusion, metal levels in samples collected from cases after PD diagnosis do not differ from control levels.[unreadable] [unreadable] Recent analyses have evaluated the role of genetic susceptibility in PD. One studied common polymorphic variants in SNCA, the gene for synuclein, a protein important in some PD lineages. Genetic variability in SNCA has been inconsistently associated with sporadic PD risk. Changes in SNCA expression have been reported for some variants, but the role of SNCA as a susceptibility factor in PD is inconclusive. We evaluated 61 SNCA variants in FAME. Variants were selected based on prior association, population frequency, and mechanistic hypotheses. Allelic associations were assessed with Fishers exact test; 2- and 3-marker haplotypes were also tested. We genotyped 100 cases and 370 controls. Three SNPs deviating from HWE and with poor call rates were excluded from analysis. Four SNPs were mono-allelic. Call rates were > 0.98 for all others. Seven SNPs were associated with PD risk (P<0.10), three directly and four inversely. Haplotypic analyses did not identify stronger associations. We conclude that common SNCA SNPs are associated with PD, although none was significant after Bonferroni correction. Our observations replicate prior reports for rs356186, rs3822086, rs2737026, and rs2736994. Other associations are either novel or conflict with prior reports. These results further support SNCA as a susceptibility locus for PD, but suggest significant population heterogeneity or environmental interaction.[unreadable] [unreadable] Another analysis combined data from FAME and PEAK, an incident case-control study based in a California HMO, to focus on the role the organic cation transporter (OCT2) gene (SLC22A2) in PD risk. OCT2, a membrane transporter with affinity for small cations including MPP+ and dopamine, is preferentially expressed in kidney, choroid plexus, olfactory mucosa and substantia nigra pars compacta dopaminergic neurons, where it may play a role in cell integrity. The A270S (rs316019) and A1506G (rs316003) variants were genotyped in FAME and PEAK. A total of 694 PD cases and 1007 controls were studied. Results for the two studies were similar. In combined analyses, both variants were inversely associated with PD. In allelic analyses, the OR for the A270S variant was 0.76 (95%CI: 0.58,0.99, p=0.043) and for the A1506 variant was 0.69 (95%CI: 0.58,0.82, p<0.001). In genotypic analyses, the association was stronger with two compared to one copy of the variant, and tests for trend were significant (p=0.047 and p<0.001, respectively). We conclude that these two variants of the OCT2 membrane transporter are inversely associated with PD risk, suggesting a role for OCT2 in the pathogenesis of PD.